The invention relates to cyclopentabenzofuran derivatives, processes for their preparation, the use of cyclopentabenzofuran derivatives for the production of a medicament for the therapy of NF-xcexaB-dependent diseases and medicaments which contain the cyclopentabenzofuran derivatives.
Extracts of the plant Aglaia elliptifolia exhibit antileukemic properties. The first active compound identified was a dihydrocyclopentabenzofuranol derivative called rocaglamide (J. Chem. Soc., Chem. Commun. 1982, 1150; U.S. Pat. No. 4,539,414). After this, several studies appeared on synthesis experiments which were finally also successful (J. Chem. Soc., Chem. Commun. 1991, 1137). Only 10 years after the isolation of rocaglamide were its insecticidal properties described (Pestic. Sci 36, 53 (1992) and Phytochemistry 32, 67 (1993)) and after that in another species, Aglaia odorata, another three derivatives only differing in one substituent were found (Phytochemistry 32, 307 (1993)). Later, for example, from the species Aglaia roxburghiana, the first four fused derivatives of rocaglamide were isolated (WO 96/04284), then numerous further new derivatives and their pharmacological properties were described (cf., for example, J. Nat. Prod. 59, 650 (1996); Tetrahedron 52, 6931 (1996); Phytochemistry 44, 1455 (1997); Phytochemistry 45 1579 (1997); Z. Naturforsch., C: Biosci. 52, Tetrahedron 52, 17625 (1997); B. W. Nugroho, Thesis, Bayer. Julius-Maximilian Univ. Wxc3xcrzburg, 1997); WO 97/08161 A1).
An important step in many inflammatory processes is the translocation of the protein xe2x80x9cnuclear factor kappa Bxe2x80x9d, in brief NF-xcexaB, into the cell nucleus and the stimulation of the expression of the genes caused thereby. whose products are responsible for inflammatory reactions (Trends Pharmacol. Sci. 18, 46 (1997)). For example, in asthma the nonbeneficial, excessive (non self-limiting) production of these proteins is responsible for the intensification and maintenance of the inflammatory process and the unpleasant to life-threatening symptoms of this disease associated therewith. Because the long-term treatment with glucocorticoids corresponding to the present state of the art is affected by some disadvantages, NF-xcexaB is seen as a compelling target for the development of new antiinflammatory active compounds against asthma.
It has now been found that the cyclopentabenzofuran derivatives of the formula (I) 
in which
R1 and R3 independently of one another in each case represent hydrogen, halogen or alkyl,
R2 and R4 independently of one another in each case represent halogen, alkyl or optionally substituted alkoxy,
R5 represents hydroxyl, alkylamino or the radical xe2x80x94NR12xe2x80x94CHR13xe2x80x94COOR14, in which
R12 represents hydrogen or alkyl,
R13 represents one of the radicals of a natural or synthetic xcex1-amino acid, where functional groups can optionally be present in protected form, or
R12 and R13 together represent xe2x80x94(CH2)3xe2x80x94 and xe2x80x94(CH2)4xe2x80x94, and
R14 represents alkyl, benzyl or another C-terminal protective group,
R6 represents hydrogen or
R5 and R6 together represent oxygen (oxo),
R7 and R8 in each case represent hydrogen,
R9 represents optionally substituted phenyl or hetaryl,
R10 represents hydrogen, halogen, alkyl or alkoxy and
R11 represents hydrogen, halogen or alkyl,
and their salts
are suitable as inhibitors of nuclear factor kappa B (NF-xcexaB)-mediated gene expression for the therapy of pathophysiological processes.
Depending on the nature of the substituents, the compounds of the formula (I) can also be present as geometrical and/or optical isomers or isomer mixtures, in different compositions, which can optionally be separated in a customary manner. Both the pure isomers and the isomer mixtures, their preparation and use, and compositions containing these are a subject of the present invention. Below, for the sake of simplicity, however, compounds of formula (I) are always referred to, although both the pure compounds and optionally also mixtures having different proportions of isomeric compounds are intended.
If, in a structural formula, the number of diastereomers is restricted by fixing the configuration on at least two chiral centers then, if not stated otherwise, in principle also the other enantiomers (mirror image) are intended.
The compounds according to the invention can also be present in the form of their salts. In general, salts with organic or inorganic bases or acids may be mentioned here.
In the context of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acid or sulfonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Those particularly preferred are, for example, sodium, potassium, magnesium or calcium salts, and also ammonium salts, which are derived from ammonia, or organic amines, such as ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
Formula (I) provides a general definition of the substances utilizable according to the invention. Preferred substituents or ranges of the radicals listed in the formulae above and below are explained in the following.
R1 and R3 independently of one another preferably in each case represent hydrogen, fluorine, chlorine, bromine or C1-C6-alkyl.
R2 and R4 independently of one another preferably in each case represent fluorine, chlorine, bromine, C1-C6-alkyl or C1-C4-alkoxy optionally substituted by fluorine or chlorine.
R5 preferably represents hydroxyl, C1-C4-alkylamino or the radical xe2x80x94NR12xe2x80x94CHR13xe2x80x94COOR14.
R6 preferably represents hydrogen.
R5 and R6 also preferably together represent oxygen (oxo).
R7 and R8 preferably in each case represent hydrogen.
R9 preferably represents phenyl, methylenedioxyphenyl or 5- or 6-membered hetaryl having 1 or 2 heteroatoms from the series consisting of nitrogen, oxygen and sulfur which in each case can optionally be substituted up to four times by substituents of the group: halogen, C1-C6-alkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, C1-C4-alkylcarbonyl, phenyl, phenoxy, hetaryl, hetaryloxy, C1-C4-alkyl substituted by fluorine or chlorine, C1-C4-alkoxy substituted by fluorine or chlorine, C1-C4-alkylthio substituted by fluorine or chlorine, C1-C4-alkylcarbonyl substituted by fluorine or chlorine.
R10 preferably represents hydrogen, fluorine, chlorine, C1-C6-alkyl or C1-C6-alkoxy.
R11 preferably represents for hydrogen, fluorine, chlorine, bromine or C1-C6-alkyl.
R12 preferably represents hydrogen or C1-C4-alkyl.
R13 preferably represents hydrogen, C1-C4-alkyl optionally substituted by amino or hydroxyl or represents mercaptomethyl, methylthioethyl, carboxmethyl, carboxyethyl, carbamoylmethyl, carbamoylethyl, guanidinopropyl or represents phenyl or benzyl optionally substituted by amino, nitro, halogen, hydroxyl or methoxy or represents naphthylmethyl, indolylmethyl, imidazolylmethyl, triazolylmethyl or pyridylmethyl, where functional groups can optionally be present in protected form.
R12 and R13 also preferably together represent xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)4xe2x80x94.
R14 preferably represents C1-C6-alkyl, benzyl or another C-terminal protected group.
R1 and R3 independently of one another particularly preferably in each case represent hydrogen, fluorine, chlorine, bromine, methyl or ethyl.
R2and R4 independently of one another particularly preferably in each case represent fluorine, chlorine, bromine, C1-C4-alkyl or methoxy or ethoxy optionally substituted by fluorine or chlorine.
R5 particularly preferably represents hydroxyl, C1-C4-alkylamino or the radical xe2x80x94NR12xe2x80x94CHR13xe2x80x94COOR14.
R6 particularly preferably represents hydrogen.
R5 and R6 also particularly preferably together represent oxygen (oxo).
R7 and R8 particularly preferably in each case represent hydrogen.
R9 particularly preferably represents phenyl, methylenedioxyphenyl or 5- or 6-membered hetaryl having 1 or 2 heteroatoms from the series consisting of nitrogen, oxygen and sulfur, which in each case can optionally be substituted up to 3 times by substituents of the group: fluorine, chlorine, bromine, iodine, C1-C4-alkyl, hydroxyl, C1-C4-alkoxy, C1-C4-alkylthio, C2-C4-alkylcarbonyl, phenyl, phenoxy, furyl, thienyl, pyrrolyl, thiazolyl, pyridyl, furyloxy, thienyloxy, pyrrolyloxy, thiazolyloxy, pyridyloxy, C1-C4-alkyl substituted by fluorine or chlorine, C1-C3-alkoxy substituted by fluorine or chlorine, C1-C3-alkylthio substituted by fluorine or chlorine, C1-C4-alkylcarbonyl substituted by fluorine or chlorine.
R10 particularly preferably represents hydrogen, fluorine, C1-C4-alkyl or C1-C4-alkoxy.
R11 particularly preferably represents hydrogen, fluorine, chlorine, bromine or C1-C4-alkyl.
R12 particularly preferably represents hydrogen or methyl.
R13 particularly preferably represents hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, 3-aminopropyl, 4-aminobutyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 3-guanidinopropyl, phenyl, benzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 3,4-dichlorobenzyl, 4-iodobenzyl, xcex1-naphthylmethyl, xcex2-naphthylmethyl 3-indolylmethyl, 4-imidazolylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, 2-pyridylmethyl or 4-pyridylmethyl, where functional groups can optionally be present in protected form.
R12 and R13 also particularly preferably together represent xe2x80x94(CH2)3xe2x80x94 or xe2x80x94(CH2)4xe2x80x94.
R14 particularly preferably represents C1-C4-alkyl, benzyl or another C-terminal protective group.
R1 and R3 very particularly preferably in each case represent hydrogen, chlorine or bromine.
R2 and R4 very particularly preferably in each case represent methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy, 1,1,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trichloro-1,1-difluoromethoxy or 1,1-difluoroethoxy, in particular methoxy or ethoxy.
R5 very particularly preferably represents hydroxyl, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino or the radical xe2x80x94NR12xe2x80x94CHR13xe2x80x94COOR14.
R6 very particularly preferably represents hydrogen.
R5 and R6 also very particularly preferably together represent oxygen (oxo).
R7 and R8 very particularly preferably in each case represent hydrogen.
R9 very particularly preferably represent phenyl, methylenedioxyphenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl or pyridyl, which in each case can optionally be monosubstituted or disubstituted by substituents of the group: fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, difluoromethyl, chlorodifluoromethyl, 2-chloro-1,1,2-trifluoroethyl, 1,1,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, 1,1-difluoro-2,2,2-trichlorcethyl, 2,2,2-trifluoroethyl, 1,1,2,3,3,3-hexafluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy, 1,1,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trichloro-1,1-difluoromethoxy, 1,1-difluoroethoxy, methylthio, ethylthio, trifluoromethylthio, 1,1-difluoroethylthio, 2,2,2-trifluoroethylthio, phenyl, phenoxy, acetyl, propionyl, propylcarbonyl, butylcarbonyl or 2-methylpropylcarbonyl.
R10 very particularly preferably represents hydrogen, fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
R11 very particularly preferably represents hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
R12 very particularly preferably represents hydrogen.
R13 very particularly preferably represents hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, 3-aminopropyl, 4-aminobutyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 3-guanidinopropyl, phenyl, benzyl, 4-hydroxybenzyl, 3-indolylmethyl or 4-imidazolylmethyl.
R14 very particularlyv preferably represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or benzyl.
The abovementioned general radical definitions and explanations or radical definitions and explanations mentioned in preferred ranges can be combined with one another in any desired manner, i.e. even between the respective ranges and preferred ranges. They apply correspondingly to the final products and also to the precursors and intermediates.
Preferred compounds of the formula (I) according to the invention are those in which a combination of the meanings (preferably) mentioned above as preferred is present.
Particularly preferred compounds of the formula (I) according to the invention are those in which a combination of the meanings mentioned above as particularly preferred is present.
Very particularly preferred compounds of the formula (I) according to the invention are those in which a combination of the meanings mentioned as very particularly preferred is present.
According to a second aspect, cyclopentabenzofuran derivatives of the formula (I) which can be used according to the invention are those in which
R1 and R3 independently of one another in each case represent hydrogen, halogen or alkyl,
R2 and R4 independently of one another in each case represent halogen, alkyl or optionally substituted alkoxy,
R5 represents hydroxyl, alkylamino or the radical xe2x80x94NR12xe2x80x94CHR13xe2x80x94COOR14, in which
R12 represents hydrogen or alkyl,
R13 represents one of the radicals of a natural or synthetic xcex1-amino acid, where functional groups can optionally be present in protected form, or
R12 and R13 together represent xe2x80x94(CH2)3xe2x80x94 and xe2x80x94(CH2)4xe2x80x94, and
R14 represents alkyl, benzyl or another C-terminal protective group,
R6 represents hydrogen or
R5 and R6 together represent oxygen (oxo),
R7 and R8 in each case represent hydrogen,
R9 represents optionally substituted phenyl or hetaryl,
R10 represents hydrogen, alkyl or alkoxy and
R11 represents hydrogen, halogen or alkyl.
According to the second aspect of the invention, compounds of the formula (I) are preferred in which
R1 and R3 in each case represent hydrogen, fluorine, chlorine, bromine, methyl or ethyl,
R2 and R4 in each case represent methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy, 1,1,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trichloro-1,1-difluoromethoxy or 1,1-difluoroethoxy,
R5 represents hydroxyl, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino or the radical xe2x80x94NR12xe2x80x94CHR13xe2x80x94COOR14,
R6 represents hydrogen, or
R5 and R6 together represent oxygen (oxo),
R7 and R8 in each case represent hydrogen,
R9 represents phenyl, methylenedioxyphenyl, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl or pyridyl, which is optionally monosubstituted or disubstituted by fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, difluoromethyl, chlorodifluoromethyl, 2-chloro-1,1,2-trifluoroethyl, 1,1,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 1,1,2,3,3,3-hexafluoropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, trifluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, 2-chloro-1,1,2-trifluoroethoxy, 1,1,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2,2,2-trichloro-1,1-difluoromethoxy or 1,1-difluoroethoxy,
R10 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy,
R11 represents hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl,
R12 represents hydrogen,
R13 represents hydrogen, methyl, iso-propyl, iso-butyl, sec-butyl, hydroxymethyl, 1-hydroxyethyl, mercaptomethyl, 2-methylthioethyl, 3-aminopropyl, 4-aminobutyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 3-guanidinopropyl, phenyl, benzyl, 4-hydroxybenzyl, 3-indolylmethyl or 4-imidazolylmethyl, and
R14 represents mcthyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, benzyl or another C-terminal protective group.
Saturated or unsaturated hydrocarbon radicals such as alkyl or alkenyl can as far as possible in each case be straight-chain or branched, even in combination with heteroatoms, such as in alkoxy.
Optionally substituted radicals can be monosubstituted or polysubstituted, where in the case of polysubstitution the substituents can be identical or different.
In the context of the invention hetaryl in general represents an aromatic optionally benzo-fused 5- to 7-membered, preferably 5- to 6-membered, heterocycle, which can contain up to 3 heteroatoms from the series consisting of S, N and/or O. Examples which may be mentioned are: indolyl, isoquinolyl, quinolyl, benzo[b]thiophene, benzo[b]furanyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, morpholinyl or piperidyl. Furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl and thienyl are preferred.
The protective groups known from peptide chemistry are mentioned, for example, in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons, New York 1991. Examples of suitable protective groups are C1-C4-alkyl and benzyl in particular for hydroxyl or carboxyl groups (C-terminal protective groups); acetyl, trifluoroacetyl, trichloroacetyl, benzoyl, phenylacetyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl, (Cbz), (9-fluorenyl)methoxycarbonyl (Fmoc) and benzyl in particular for hydroxyl and amino groups (N-terminal protective groups).
Of these, those particularly preferred are tert-butyl, benzyl, acetyl, Boc and Cbz.
The abovementioned substances of the formula (I) which can be used according to the invention are new with the exception of 3,3a-dihydro-6,8-dimethoxy-3a-(4-methoxyphenyl)-3-phenyl-1H-cyclopenta[b]benzofuran-1,8b(2H)-diol and 2,3,3a,8b-tetrahydro-8b-hydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-3-phenyl-1H-cyclopenta[b]benzofuran-1-one (cf. J. Chem. Soc., chem. Commun. 1991, 1137; J. Chem. soc. Perk. Trans. 1, 1992, 2657).
It has furthermore been found that the new compounds of the formula (I) can be obtained by one of the processes described below.
A) cis-Dihydrocyclopentabenzofurandiols of the formula (I-a) 
xe2x80x83in which
R1, R2, R3, R4, R9, R10 and R11 have the meanings indicated above,
xe2x80x83can be prepared by subjecting ketoaldehydes of the formula (II-a) 
xe2x80x83in which
R1, R2, R3, R4, R9, R10 and R11 have the meanings indicated above,
xe2x80x83to reductive cyclization.
B) Tetrahydrocyclopentabenzofuranones of the formula (I-b) 
xe2x80x83in which
R1, R2, R3, R4, R9, R10 and R11 have the meanings indicated above,
xe2x80x83can be prepared by
oxidizing dihydrocyclopentabenzofurandiols of the formula (I-a) 
xe2x80x83in which
R1, R2, R3, R4, R9, R10 and R11 have the meanings indicated above.
C) trans-Dihydrocyclopentabenzofurandiols of the formula (I-c) 
xe2x80x83in which
R1, R2, R3, R4, R9, R10 and R11 have the meanings indicated above,
xe2x80x83can be prepared by
reducing tetrahydrocyclopentabenzofuranones of the formula (I-b) 
xe2x80x83in which
R1, R2, R3, R4, R9, R10 and R11 have the meanings indicated above,
with alkali metal or tetraalkylammonium acyloxyborohydrides.
D) Cyclopentabenzofuran derivatives of the formula (I-d) 
xe2x80x83in which
R1 to R11 have the meanings indicated above, with the restriction that at least one of the radicals R1, R3 and R11 represents halogen or alkyl,
can be prepared by introducing this or these radicals by electrophilic aromatic substitution of compounds of the formula (I) indicated above, in which the radical or radicals to be substituted represent(s) hydrogen.
E) Cyclopentabenzofuran derivatives of the formula (I-e) 
xe2x80x83in which
R1 to R4 and R9 to R11 have the meanings indicated above and
R5-1 represents alkylamino or the radical xe2x80x94NR12xe2x80x94CHR13xe2x80x94COOR14, in which
R12, R13 and R14 have the meanings indicated above,
can be prepared by
reacting tetrahydrocyclopentabenzofuranones of the formula (I-b) 
xe2x80x83in which
R1 to R4 and R9 to R11 have the meanings indicated above,
with primary amines or amino acid derivatives of the formula (III)
Hxe2x80x94R5-1xe2x80x83xe2x80x83(III),
xe2x80x83in which
R5-1 represents alkylamino or the radical xe2x80x94NR12xe2x80x94CHR13xe2x80x94COOR14, in which
xe2x80x83R12, R13 and R14 have the meanings indicated above,
in the presence of a reducing agent.
If, for example, 2,3-dihydro-4,6-diethoxy-2-(4-methoxyphenyl)-3-oxo-xcex2-phenyl-2-benzofuranpropanal is used as a starting substance, the successive reaction courses of the processes (A), (B) and (C) according to the invention here can be shown by the following equation: 
If, for example, 3,3a-dihydro-6,8-dimethoxy-3a-(4-methoxyphenyl)-3-phenyl-1H-cyclopenta[b]benzofuran-1,8b(2H)-diol is used as a starting compound and bromine-pyridine complex as a reagent, the reaction course of process (D) according to the invention can be shown by the following equation: 
If, for example, 2,3,3a,8b-tetrahydro-8b-hydroxy-6,8-dimethoxy-3a-(4-methoxyphenyl)-3-phenyl-1H-cyclopenta[b]benzofuran-1-one and glycine methyl ester hydrochloride are used as starting substances and tetramethylammonium trisacetoxyborohydride in the presence of molecular sieve is used as a reagent, the reaction course of process (E) according to the invention can be shown by the following equation: 
Formula (II-a) provides a general definition of the ketoaldehydes needed for carrying out process (A) according to the invention. In this formula, R1 to R11 preferably have those meanings which have already been mentioned as preferred in connection with the description of the cyclopentabenzofuran derivatives of the formula (I). The ketoaldehydes of the formula (II-a) and the other diastereomers of the formula (II-b) indicated further below are new with the exception of 2,3-dihydro-4,6-dimethoxy-2-(4-methoxyphenyl)-3-oxo-xcex2-phenyl-2-benzofuranpropanal.
Ketoaldehydes of the formulae (II-a) and (II-b) can be prepared, for example, by adding benzofuranones of the formula (IV) to cinnamaldehyde or its heterocyclic analogs of the formula (V) in the presence of an acid-binding agent, such as benzyltrimethylammonium hydroxide solution or sodium methoxide and in the presence of a diluent, such as methanol or tert-butanol, according to the following reaction scheme: 
The diastereomers (II-a) and (II-b) can be separated by column chromatography according to customary methods.
The vinylogous arylaldehydes of the formula (V) are in some cases commercially obtainable, are known or can be prepared according to known methods.
Benzofuranones of the formula (IV) can be prepared, for example, by Hoesch reaction of cyanohydrins (cf. Chem. Soc. Perkin Trans. I, 1992, 2657) or preferably trimethylsilylcyanohydrins (cf. Preparation examples) of the formula (VI) of 4-substituted benzaldehydes, in which R15 represents hydrogen or trimethylsilyl (TMS), with phenols of the formula (VII) according to the following reaction scheme: 
The benzaldehydes of the formula (VIII) and phenols of the formula (VII) needed for this are generally known compounds of organic chemistry. The reaction of the benzaldehydes to give the cyanohydrins of the formula (VI) is carried out, for example, using sodium cyanide or trimethylsilyl cyanide according to known methods.
An example of the derivatization of the radicals R2 and R4 at the stage of the benzofuranone of the formula (IV) is alkylation (e.g. with diethyl sulfate/potassium carbonate) with subsequent cleavage of the resulting enol ether (e.g. with hydrochloric acid) according to the following reaction scheme: 
The dihydrocyclopentabenzofurandiols of the formula (I-a) needed for carrying out process (B) according to the invention are subsets of the compounds of the general formula (I) according to the invention and can be prepared, for example, by processes (A) or (D).
The tetrahydrocyclopentabenzofuranones of the formula (I-b) needed for carrying out processes (C) and (E) according to the invention are subsets of the compounds of the general formula (I) according to the invention and can be prepared, for example, by process (B) or (D).
The cyclopentabenzofurans needed for carrying out process (D) according to the invention are subsets of the compounds of the general formula (I) according to the invention and can be prepared, for example, by process (A), (C) or (E).
Formula (III) provides a general definition of the amines or amino acid derivatives needed for carrying out process (E) according to the invention. In this formula, R5-1, if applicable, and also R12 to R14 preferably has those meanings which have already been mentioned as preferred for R5 and also R12 to R14 in connection with the description of the cyclopentabenzofuran derivatives of the formula (I). The compounds of the formula (III) are mainly commercially obtainable or can be prepared by known methods of amino acid chemistry.
Process (A) according to the invention is carried out in the presence of a reducing agent. Samarium diiodide is preferably used for this purpose. Samarium diiodide can be employed as a solution (0.1 M) in THF or by reaction of samarium with 1,2-diiodoethane in solution.
Process (A) according to the invention is preferably carried out in the presence of a diluent. Those suitable are organic solvents such as, for example, aromatic hydrocarbons such as benzene or toluene or ethers such as tetrahydrofuran or dioxane.
Process (B) according to the invention is carried out as a Swem or Parikh-Doering oxidation. The reagents employed are, for example, dimethyl sulfoxide and oxalyl chloride/triethylamine or sulfur trioxide-pyridine complex and triethylamine.
Process (B) according to the invention is preferably carried out in the presence of a diluent. Those suitable are organic solvents such as, for example, ethers such as diethyl ether, tetrahydrofuran or dioxane or sulfoxides such as dimethyl sulfoxide.
The alkali metal or tetraalkylammonium acyloxyborohydrides needed for carrying out process (C) according to the invention are, for example, lithium, sodium, potassium or C1-C4-tetraalkylammonium salts of tris-C1-C5-(halogeno)alkylcarbonyloxyborohydrides such as sodium trisacetoxyborohydride or tetramethylammonium trisacetoxyborohydride. The reducing agents can also be prepared in situ by employing, for example, lithium borohydride or sodium borohydride and the carboxylic acid corresponding to the desired acyl radical, such as acetic acid, trifluoroacetic acid or propionic acid.
Process (C) is preferably carried out in the presence of a diluent. Organic solvents are suitable for this purpose. The following may be mentioned by way of example: nitrites, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; carboxylic acids such as acetic acid or propionic acid.
Process (D) according to the invention comprises halogenations and Friedel-Crafts alkylations. Suitable reagents are, for example: chlorine, bromine, bromine-pyridine complex, N-bromosuccinimide, I,I-bis(trifluoroacetoxy)-iodobenzene, alkyl chlorides and alkyl bromides.
Process (D) is preferably carried out in the presence of a diluent. Organic solvents are suitable for this purpose. The following may be mentioned by way of example: aliphatic or alicyclic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane or decalin; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene, methylene chloride, chloroform, tetrachloromethane, dichloroethane, trichloroethane or tetrachloroethylene; ethers, such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane, diethylene glycol dimethyl ether or anisole; nitriles, such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile.
Process (D) is optionally carried out in the presence of a Lewis acid as a catalyst. Examples which may be mentioned are: iron (in brominations) iron chlorides and bromides, aluminum chloride and bromide, zinc chloride or boron trifluoride.
The reactions of the processes according to the invention can be carried out at normal pressure or at elevated pressure. They are preferably carried out at normal pressure. They are carried out, worked up and the reaction products are isolated according to generally customary, known methods. The final products are preferably purified by crystallization, chromatographic separation or by removal of the volatile constituents, optionally in vacuo (cf. also the Preparation examples).
The substances utilizable according to the invention are low molecular weight inhibitors which selectively inhibit nuclear factor kappa B (NF-xcexaB)-mediated pathophysiological processes. NF-xcexaB-mediated processes occur in inflammatory diseases, immunological disorders, septic shock, transplant rejection, radiation damage, reperfusion injuries after ischemia, stroke and cerebral trauma, thromboses, cirrhosis of the liver, asthma or in complex, chronic inflammatory disorders such as arteriosclerosis and multiple sclerosis.
The Pharmacological Action of Inhibitors of Nuclear Factor Kappa B
Nuclear factor kappa B (NF-xcexaB) is a dimeric protein complex occurring in many tissue cells and in particular in blood cells. NF-xcexaB takes on a particular role in the control of the expression of genes which have an NF-xcexaB binding sequence (5xe2x80x2-GGGPuNNPyPyCC-3xe2x80x2) in their promoter sequence. To this extent, NF-xcexaB is a transcription factor. The physiological activity of NF-xcexaB in the control of gene expression, however, is subject to a regulation principle, in which NF-xcexaB is released from a complex with the protein IxcexaB in order to be translocated as a transcription factor in the cell nucleus of gene activation. The regulation principle for the release of active NF-xcexaB from a complex with the protein IxcexaB is still not known in detail.
Likewise, it is not known how the formation of homodimeric and heterodimeric NF-xcexaB protein complexes takes place. NF-xcexaB acts on gene activation as a dimeric transcription factor. The dimerization can take place under the structurally related transcription factors Rel A, Rel B, c-Rel, p50 or p52, which form a family of transcription factor proteins. In the dimerization of the subunits to the NF-xcexaB, there can also already be a regulation principle for the control of the genes later described in greater detail, which is still not known.
A crucial fcature of NF-xcexaB compared to other transcription factors is that NF-xcexaB is a primary transcription factor. Primary transcription factors are already present in the cell in inactive (usually complex-bound) form and are released after an appropriate stimulus in order to be able to display their action very rapidly. Primary transcription factors are not first formed by the activation of the associated gene and subsequent transcription and translation.
This property of NF-xcexaB, the formation of homodimeric or heterodimeric Rel proteins and the formation of an inactive protein complex with an IxcexaB protein, offer very different points of attack for phannacologically active substances than the points of attack of the de novo biosynthesis of transcription factors. For the sake of completeness, it may be mentioned that the genes for the formation of NF-xcexaB (genes of the Rel family) and the genes for the formation of the IxcexaB proteins (gene family comprising the genes for IxcexaB-xcex1, IxcexaB-xcex2, p105/IxcexaB-xcex3, p100/IxcexaB-xcex4, IxcexaB-xcex5 and others) for their part are of course also subject to regulation, which can be points of attack for pharmaceutically active substances. Thus it is known that the expression of the constitutively formed IxcexaB proteins p105 and p100 is increased by stimuli which also activate NF-xcexaB, such as tumour necrosis factor-xcex1 (TNF-xcex1) or phorbol myristate acetate (PMA).
A regulation mechanism is described in the literature in which it is shown that the overexpression of IxcexaB binds active NF-xcexaB and thus inactivates it. This also applies if the NF-xcexaB has already entered into a complex with the DNA (P. A. Baeuerle, T. Henkel, Annu. Rev. Immunol. 12, 141-179, 1994). From this it can be concluded that there are a number of specific points of attack in the biochemical function of NF-xcexaB and IxcexaB proteins which should make it possible to inhibit an undesirable, pathophysiological, NF-xcexaB-dependent gene activation selectively.
A chemical compound which selectively inhibits the function of NF-xcexaB or the function of IxcexaB proteins or IxcexaB genes to an increased extent should be able to be uscd as a pharmaceutical for the suppression of NF-xcexaB-mediated disease processes.
Primarily, NF-xcexaB can promote all pathophysiological processes in which genes are involved which have the NF-xcexaB binding sequence in their promoter. Mainly, these are genes which play a crucial causal role in immunological complications, in inflammatory diseases, autoimmune disorders, septic shock, transplant rejection, thromboses or else alternatively in chronic inflammatory diseases such as arteriosclerosis, arthritis and rheumatism psoriasis.
NF-xcexaB binding sequences contain, for example, the promoters of receptors of lymphoid cells (T-cell receptors), of MHCI and MHCII genes, of cell adhesion molecules (ELAM-1, VCAM-1, ICAM-1), of cytokines and growth factors (see also the following table). Furthermore, NF-xcexaB binding sequences are found in the promoters of acute phase proteins (angiotensinogen, complement factors and others).
A chronically increased or acutely overshooting activation of the genes mentioned leads to various pathophysiological processes and syndromes.
The rapid and overshooting production of cytokines of the inflammatory reaction (TNFxcex1, interleukin-2, interleukin-4, interleukin-6, interleukin-8 and others) and of the adhesion molecules (ELAM-1, VCAM-1) in leukocytes, in particular in macrophages and also in endothelial cells, is a causal feature of processes which often run a fatal course in the case of septic shock; or in the case of radiation damage and in the case of transplant rejection often leads to considerable complications. Inhibitors which prevent the NF-xcexaB-mediated gene expression intervene very early in some diseases in the expression of pathophysiological changes and can therefore be a very effective therapeutic principle. An example is also NF-xcexaB inhibitors for diseases which are to be attributed to an overexpression of acute-phase proteins. An undesirable overexpression of acute-phase proteins can cause a complex general reaction in which tissue damage of very different types, fever and local symptoms such as inflammation and necroses can occur. Usually, the blood picture is changed. NF-xcexaB strongly induces, for example, the serum amyloid A precursor protein in the liver in the course of induction of acute-phase proteins.
For example, the NF-xcexaB-mediated gene expression of the interleukin-2-(II-2) gene can be inhibited.
Interleukin-2 is a cytokine which plays a central role in various inflammatory processes, inter alia, as a hematopoietic growth factor (Annu. Rev. Immunol. 12 141 (1994)). The promoter of the interleukin-2 gene is NF-xcexaB dependent. An inhibitor of NF-xcexaB stimulation thus opens up the possibility of preventing overshooting of II-2 production and thus of treating inflammatory processes.
In the case of other syndromes such as tissue damage after reperfusion or cirrhosis of the liver, inhibitors of NF-xcexaB-mediated gene expression can likewise represent an important therapeutic advance. There is evidence that NF-xcexaB-controlled genes are induced as a result of oxidation reactions which lead to oxidative stress after reperfusion of ischemic tissue. In this way, an overexpression of cytokines and cell adhesion molecules in the ischemic tissue causes excessive recruitment of infiltrating lymphocytes. The recruited lymphocytes contribute causally to the tissue damage.
The involvement of NF-xcexaB-controlled gene expression is evident in a number of neurodegenerative disorders. In particular in the case of nervous diseases in which the redox state of cells of the neuronal tissue is disturbed, a therapeutic benefit is ascribed to the selective inhibition of genes having an NF-xcexaB binding sequence. A disturbed redox state of neuronal cells is assumed in the case of amyotropic lateral sclerosis and in Down""s syndrome.
It is known that NF-xcexaB is a frequently encountered transcription factor in neuronal tissue and that NF-xcexaB is a redox potential-controlled transcription factor in the brain (P. A. Bauerle, T. Henkel, Annu. Rev. Immunol. 12, 141-179, 1994). A formulation of the genes which are induced by NF-xcexaB is shown in Table 1.
In addition to the already mentioned genes, whose activity is controlled by the release of NF-xcexaB and which particularly play a role in inflammatory processes, septic shock and transplant rejection, NF-xcexaB-controlled genes in viruses may also be mentioned and those which produce oncogenic cellular changes (oncogenes such as c-myc, c-rel, melanoma growth stimulating activity MGSA). In these genes too, selective inhibition of NF-xcexaB binding is a promising, therapeutically utilizable concept. The gene expression of lymphotrophic viruses such as HIV, HTLV and Epstein-Barr virus is activated either directly or by NF-xcexaB or NF-xcexaB is induced in the infected host cell, which is favourable to virus replication. In addition, HIV has an NF-xcexaB-positive action on gene expression in the cytomegalovirus (CMV) and adenovirus. Antiviral effects with NF-xcexaB inhibitors are conceivable here too.